Virtually all forms of heart failure are characterized at the cellular level by abnormalities in growth and survival of cardiac myocytes. Animal studies have shown that the epidermal growth factor Neuregulin-1 (NRG-1) is a critical regulator of these processes. NRG-1 is released from microvascular endothelial cells and acts as a paracrine growth factor via the ErbB family of tyrbsine kinase receptors expressed in cardiac myocytes to regulate myocyte growth, differentiation, and the stress response.
Important insights come from the cardiotoxic side effects of the chemotherapeutic agent trastuzumab (Herceptin®), a monoclonal antibody directed against ErbB2 (Her2) that blocks NRG-1/ErbB signaling and is used to treat receptor-positive breast carcinoma. Exposure to trastuzumab can induce a clinically significant cardiomyopathy that often reverses after discontinuation of therapy.
From a public health standpoint, cardiac remodeling is the central feature of congestive heart failure, which accounts for 6.5 million hospital days each year. Heart failure has now become the fourth leading cause of adult hospitalizations in the US, and in adults greater than 65 years of age, it is the leading cause of hospitalizations. Five million Americans suffer from chronic heart failure, and the prevalence of this condition is rising. Overall, the prognosis for heart failure patients is poor. In 2001, nearly 53,000 patients died of heart failure as the primary cause, and the number of heart failure deaths has increased over time.
Currently, novel mechanistic biomarkers can improve our understanding of the complex syndrome of heart failure and might be more useful as a multimarker strategy for establishing diagnosis, prognosis, and monitoring response to therapy.
Chemotherapy utilized in the treatment of breast cancer has potential negative effects on specific organs, with cardiac toxicity being a devastating complication associated with a poor prognosis. As both the incidence of breast cancer rises and the survival rates of patients improve, the magnitude of the problem has become increasingly significant. More than 2 million breast cancer survivors in the US alone are at risk for cardiotoxicity with the cardiovascular disease risk potentially exceeding that of recurrent cancer. Monoclonal antibodies such as trastuzumab, used to treat ErbB2 (Her-2) positive breast cancers, are associated with a 4-27% rate of heart failure and cardiac dysfunction worsened by anthracyclines.
Currently there is a lack of an established marker that is able to identify individuals at high risk of adverse cardiac events with exposure to chemotherapy. Accordingly, there exists a need to identify specific mechanistic biomarkers that are able to discriminate patients at risk for heart-failure and cardiac dysfunction when exposed to chemotherapy.